CN109053854B - 基于知母菝契皂苷元结构的衍生物、药物组合物及其应用 - Google Patents
基于知母菝契皂苷元结构的衍生物、药物组合物及其应用 Download PDFInfo
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Abstract
本发明涉及一种基于知母菝契皂苷元结构的衍生物，其结构式如通式I所示，
Description
技术领域
本发明涉及医药技术领域，特别涉及药物化学合成领域，具体是指一种基于知母菝契皂苷元结构的衍生物、其药物组合物及其应用。
背景技术
知母是我国常见的中药之一，它是百合科植物知母Anemarrhena asphodeloidesBunge的干燥块茎，具有消渴热中、除邪气、消除肢体浮肿之功效，为常用的滋阴药之一。它的提取物已经被证明具有利尿、抗糖尿病、抗血小板凝集、抗真菌等生物活性，而且也表现出对环腺苷酸磷酸二酯酶的抑制作用。
癌症是目前危害人类健康最主要的疾病之一，全球约有15％的人类死亡都是由癌症引起的。现在癌症的治疗手段主要有手术切除、放射性疗法、化学疗法或这些方法的并用，但在很大程度上仍以化学疗法为主。癌症的产生和发展是外界环境因素与遗传物质相互作用的结果。恶性肿瘤的形成与发展的重要基础是细胞的失控增殖与转移扩散，因此可以通过控制细胞凋亡的途径与发放从而达到治疗肿瘤疾病的目的，这也是目前治疗癌症的一种重要手段。随着众多学科的发展，抗癌药物的种类明显增多，有细胞毒类药物、激素类药物、生物反应调节剂、单克隆抗体药物等。寻找高效、高选择性、低毒、无耐药性并且急需的新型抗癌药物仍然极具挑战性，且相当迫切。中国具有丰富的中药资源，一些天然产物也有被用于抗肿瘤治疗的，比如喜树碱。螺甾烷皂苷已被证明具有多种活性，比如：抗菌、抗病毒、抗真菌、抗炎活性，还能抗血小板聚集、抗糖尿病和良好的细胞毒性。
诱导恶性肿瘤细胞向正常表型分化是肿瘤治疗的新途径之一，寻找低毒高效的分化诱导剂是诱导分化治疗的关键。一些天然产物如人参皂苷等能诱导多种恶性细胞的表型逆转，包括白血病细胞、畸胎瘤细胞、肝癌细胞等。这说明天然产物在对癌细胞的诱导分化方面具有一定的应用前景。
所以，用于制备抗癌药物的知母菝契皂苷元结构的衍生物是十分具有实用价值的。
发明内容
本发明的目的是为了克服上述现有技术中的缺陷，提供可用于基于知母菝契皂苷元结构的衍生物，并提供了知母菝契皂苷元结构的衍生物的合成路线。
为了实现上述目的，本发明第一方面提供了一种基于知母菝契皂苷元结构的衍生物，其中所述的衍生物具有下述通式(I)的化合物
其中，Z为单杂环、双杂环或NR1R2，杂原子可以是硫、氧、NH或NRa中的一个或2个；R1和R2各自独立为氢、取代或未取代的C1-C10烷基；R1和R2可以一起形成三至八元环，该三至八元环可被一个或多个取代基取代，取代基选自C1-C10烷基、C3-C10环烷基、C6-C20芳基、或C3-C14杂芳基、卤素、羟基、氨基、硝基、氰基、醛基、羧基、烷氧基、-CF3、-SF5或三至八元杂环，杂原子可以是硫、氧、NH或NRa；
X为C(Rb)(Rc)、C(O)或S(O)2；Rb和Rc可以一起形成三至八元碳环或杂原子为硫、氧、N、NH或NRa的三至八元杂环，该环可被一个或多个取代基取代，取代基选自C1-C10烷基、C3-C10环烷基、C6-C20芳基、或C3-C14杂芳基、卤素、羟基、氨基、硝基、氰基、醛基、羧基、烷氧基、-CF3、-SF5或杂原子为O、S、NRa中的一个或两个的三至八元杂环，其中。
Y为C(Rd)(Re)、C(O)或S(O)2；Rd和Re可以一起形成三至八元环或三至八元杂环，杂原子可以是硫、氧、NH或NRa；
Ra、Rb、Rc、Rd、Re独立地为无取代基或包括至少一个取代基的C1-C10烷基、C3-C10环烷基、C6-C20芳基、或C3-C14杂芳基，其中的取代基包括：卤素、羟基、氨基、硝基、氰基、醛基、羧基、烷氧基、-CF3、-SF5；
Rb和Rd可以被一个化学键连接；
n为0至10的整数；
m为0或1。
优选地，所述的衍生物的结构式如通式II所示：
式中，Y、R1、R2、n的定义如上述。
优选地，所述的衍生物的结构式如通式III所示：
式中，R1、R2的定义如上述。
在另一优选例中，所述的衍生物的结构式如通式IV所示：
式中，R1、R2的定义如上述。
优选地，所述衍生物为以下化合物、以下化合物的非对映异构体混合物或以下化合物的对映异构体中的一种：
优选地，所述的衍生物包括其上任何一个或多个氢原子被其稳定同位素氘取代而产生的相应氘代化合物。
本发明的另一方面，提供一种药物组合物，所述药物组合物包含：上述的通式I化合物、其药学上可接受的盐、立体异构体、互变异构体、前药或其药学上可接受的载体；优选地，还包括抗肿瘤药物，所述的抗肿瘤药物包括化疗药物、靶向肿瘤治疗药物或肿瘤治疗抗体药物中的一种或多种。
优选地，所述药学上可接受的盐选自下组：盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、甲磺酸盐、三氟甲磺酸盐、苯磺酸盐、对甲苯磺酸盐(甲苯磺酸盐)、1-萘磺酸盐、2-萘磺酸盐、乙酸盐、三氟乙酸盐、苹果酸盐、酒石酸盐、柠檬酸盐、乳酸盐、草酸盐、琥珀酸盐、富马酸盐、马来酸盐、苯甲酸盐、水杨酸盐、苯乙酸盐、扁桃酸盐。
优选地，所述抗肿瘤药物包括但不限于癌症的免疫治疗药物：PD-1抗体，CTLA-4抗体，PD-L1抗体，PD-L2抗体，任何一种其它化疗药物或靶向治疗药物，例如激酶抑制剂。
本发明还提供了一种所述的化合物在治疗癌症、眼疾、心理障碍、抑郁症、焦虑症、老年痴呆症和/或自身免疫性疾病的应用。
优选地，所述癌症包括但不限于：结肠癌、乳腺癌、胃癌、肺癌、大肠癌、胰腺癌、卵巢癌、前列腺癌、肾癌、肝癌、脑癌、黑色素瘤、多发性骨髓瘤、慢性粒细胞性白血病、血液肿瘤、淋巴肿瘤，包括在其他远离肿瘤原发部位的组织或器官的转移病变。
采用本发明的基于知母菝契皂苷元结构的衍生物、药物组合物及其应用，通过对知母皂苷元结构进行了系统性地修饰和衍生化，结合相关肿瘤细胞抑制活性测试，意外地发现很多衍生化合物具有优越的肿瘤细胞抑制活性，特别是对于多种脑肿瘤细胞的生长有着出乎意料的高抑制活性，对于治疗多种癌症具有潜在的广泛用途和巨大价值，弥补了现有技术在知母皂苷元结构修饰的衍生物的不足，具有重要科学和商业应用价值。
具体实施方式
为了能够更清楚地理解本发明的技术内容，下面对本发明的具体实施方法作进一步说明。
本发明中的术语“烷基”，是指一价饱和脂族烃基，具有1至10个碳原子，包括直链和支链烃基，如甲基(CH3-)、乙基(CH3CH2-)、正丙基(CH3CH2CH2-)、异丙基((CH3)2CH-)、正丁基(CH3CH2CH2CH2-)、异丁基((CH3)2CHCH2-)、仲丁基((CH3)(CH3CH2)CH-)、叔丁基((CH3)3C-)、正戊基(CH3CH2CH2CH2CH2-)、新戊基((CH3)3CCH2-)。
在本发明中，术语“烷基”包括取代或未取代的烷基。
在本发明中，术语“取代或未取代的”指所述基团可以是未取代的，或者所述基团中的H被一个或多个(较佳地1～6个，更佳地1～3个)取代基所取代。
在本发明中，所述的“取代的”指所述基团具有一个或多个(较佳地1～6个，更佳地1～3个)选自下组的取代基：卤素、羟基、-NH2、硝基、-CN、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基、C3-C6环烷基、C2-C4链烯基、C2-C4炔基、苯基、苄基。
在本发明中，术语“环烷基”表示取代或未取代的C3-C12环烷基。
在本发明中，术语“烷氧基”指-O-烷基，其中所述烷基可以是饱和或不饱和的、可以是支链、直链的、或环状的。优选地，烷氧基具有1～10个碳原子，较佳地1～6个碳原子。代表性的例子包括(但并不限于)：甲氧基、乙氧基、丙氧基。
在本发明中，术语“芳基”是指6至20个(较佳6～14个)碳原子的单价芳香族碳环基团，它具有单环(如苯基)或稠环(如萘基或蒽基)，如果连接点在芳香碳原上，稠环可能是非芳香性的(如2-苯并噁唑酮，2H-1,4-苯并噁嗪-3(4H)-酮-7-基等)。优选的芳基包括苯基和萘基。该术语包括取代或未取代的形式，其中取代基的定义如上。
在本发明中，术语“烯基”是指具有2至10(如2至6或2至4)个碳原子的烯基，且具有至少1(如1至2)个不饱和烯键(>C＝C<)。这类基团的例如有乙烯基、烯丙基、丁-3-烯基。
在本发明中，术语“环烷基”是指具有3至10个碳原子的、具有单环或多环(包括稠合体系，桥环体系和螺环体系)的环状烷基。在稠环体系中，一个或多个环可以是环烷基、杂环的、芳基或杂芳基，只要连接位点是通过环烷基的环。合适的环烷基的例子包括：例如，金刚烷基、环丙基、环丁基、环戊基和环辛基。
在本发明中，术语“卤代”或“卤素”是指氟、氯、溴和碘。
在本发明中，术语“杂芳基”是指环内具有1至10个碳原子和1至4个选自氧、氮和硫的杂原子的芳香基团，这样的杂芳基可以是单环的(如吡啶基或呋喃基)或稠环(如吲嗪基(indolizinyl)或苯并噻吩基)，其中，所述稠环可以是非芳香性的和/或含有一个杂原子，只要连接点是通过芳香性杂芳基的原子。在一实施例中，杂芳基的环原子氮和/或硫任选地被氧化为N-氧化物(N-O)，亚磺酰基或磺酰基。优选地杂芳基包括吡啶基、吡咯基、吲哚基、噻吩基和呋喃基。该术语包括取代或未取代的杂芳基。
在本发明中，术语“取代的杂芳基”是指被1至5个、优选1至3个、更优选1至2个的取代基所取代的杂芳基，所述取代基选自与取代的芳基所定义的相同取代基。
在本发明中，术语“杂环”或“杂环的”或“杂环烷基”或“杂环基”是指饱和的、部分饱和的或不饱和的基团(但不是芳香性的)，具有单环或稠环(包括桥环体系和螺环体系)，环内具有1至10个碳原子和1至4个(如3个)选自氮、硫或氧的杂原子，在稠环体系中，一个或多个环可以是环烷基、芳基或杂芳基，只要连接点通过非芳香性环。在一实施例中，杂环基团的氮原子和/或硫原子任选地被氧化，以提供N-氧化物、亚磺酰基和磺酰基部分。
在本发明中，术语“取代的杂环的”或“取代的杂环烷基”或“取代的杂环基”是指被1到5(如1至3)个取代基所取代的杂环基团，所述取代基与取代的环烷基所定义的取代基相同。
在本发明中，术语“立体异构体”是指一个或多个立体中心的手性不同的化合物。立体异构体包括对映异构体和非对映异构体。
在本发明中，术语“互变异构体”是指质子位置不同的化合物的替代形式，如烯醇-酮和亚胺-烯胺互变异构体，或杂芳基的互变异构形式，所述杂芳基包含与环的-NH-部分和环的N-部分连接的环原子，如吡唑、咪唑、苯并咪唑、三唑和四唑。
本发明提供了一种药物组合物，它包含安全有效量范围内的活性成分，以及药学上可接受的载体。
本发明所述的“活性成分”是指本发明所述的通式(I)化合物或其药学上可以接受的盐、其立体异构体或其互变异构体、或其前药。
本发明所述的“活性成分”和药物组合物可用作IDO抑制剂。在另一优选例中，用于制备预防和/或治疗肿瘤的药物。在另一优选例中，用于制备预防和/或治疗IDO介导的疾病的药物。
“安全有效量”指的是：活性成分的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1～2000mg活性成分/剂，更佳地，含有10～200mg活性成分/剂。较佳地，所述的“一剂”为一个药片。
“药学上可接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的活性成分以及它们之间相互掺和，而不明显降低活性成分的药效。
本发明优选实施例的化合物可以作为单独活性药剂给药，也可以与一个或多个其它用于治疗癌症的试剂组合使用。
本发明优选实施例的化合物与已知的治疗剂和抗癌剂组合使用也是有效的，目前已知的化合物和其它抗癌剂或化疗剂的组合在优选实施例范围之内。这类药剂的例子可参见《癌症原理和实践肿瘤学》(Cancer Principles and Practice of Oncology)，V.T.Devita和S.Hellman(编者)，第6版(2001年2月15日)，Lippincott Williams&Wilkins出版社。基于药物的特殊性质和所涉及的癌症，本领域普通技术人员能够辨别有效的药剂组合。这种抗癌剂包括(但不限于)如下：雌激素受体调节剂、雄激素受体调节剂、视黄醇类受体调节剂、细胞毒性/细胞生长抑制剂、抗增殖剂、异戊烯基蛋白转移酶抑制剂、取乙酰酶(HDAC)抑制剂、HMG-CoA还原酶抑制剂和其他血管生成抑制剂、细胞增殖和生存信号抑制剂、凋亡诱导剂和干扰细胞周期检查点(cell cycle checkpoint)的试剂、CTLA4抗体、PD-1抗体、PD-L1抗体等。优选实施例的化合物与放射治疗同时施用时也有效。
通常，优选实施例的化合物将以治疗有效量、通过具有类似作用的药剂的任意一种可接受的模式施用。优选实施例的化合物(即活性成分)的实际用量根据多个因素确定，如待治疗疾病的严重程度、患者的年龄和相对健康程度、被使用化合物的效力、施用的路径和形式，以及其他因素。该药物可一天施用多次，优选地，每天一次或两次。所有这些因素都在主治医生的考虑范围内。
优选实施例的目的，治疗有效剂量通常可以是对患者一次性施用或分次施用的每日总剂量，例如，每日约0.001至约1000毫克/公斤体重，优选地，每日约1.0至约30毫克/千克体重。单位剂量组合物(Dosage unit composition)可包含其剂量因数以形成每日剂量。剂型的选择取决于各种因素，例如给药模式和药物物质的生物利用度。通常，优选实施例的化合物可作为药物组合物通过以下任意一种路线给药：口服、全身给药(如透皮、鼻内或通过栓剂)、或肠外给药(如肌内、静脉内或皮下)。优选的给药方式为口服，可根据苦的程度调节方便的日剂量。组合物可采取的形式为片剂、丸剂、胶囊、半固体、粉剂、缓释制剂、溶液、悬浮液、酏剂、气雾剂或任何其他适当的组合物。另一种优选的施用优选实施例化合物的方式为吸入。这是一种将治疗剂直接运送给呼吸道的有效方法(参见，如美国专利号5,607,915)。
合适的药学上可接受的载体或赋形剂包括：如处理剂和药物运送改性剂和促进剂，诸如磷酸钙、硬脂酸镁、滑石、单糖、二糖、淀粉、明胶、纤维素、甲基纤维素钠、羧甲基纤维素、葡萄糖、羟丙基-B-环糊精、聚乙烯吡咯烷酮、低熔点蜡、离子交换树脂等，及其任意两种或多种的组合。液体和半固体的赋形剂可以选自甘油、丙二醇、水、乙醇和各种油，包括石油、动物油、植物油或合成来源，如花生油、豆油、矿物油、芝麻油等。优选的液体载体，特别是用于可注射溶液的载体，包括水、盐水、葡萄糖水性溶液和乙二醇。其它适宜的药学上可接受的赋形剂在《雷明顿药物科学》(Remington’s Pharmaceutical Sciences),MackPub.Co.,新泽西(1991)有描述，通过引用纳入本文。
在本发明中，术语“药学上可接受的盐”是指通式I化合物的非毒性酸或碱土金属盐。这些盐可在最终分离和纯化通式I化合物时原位制得、或分别将合适的有机或无机酸或碱与碱性或酸性官能团反应制得。代表性的盐包括，但不限于：乙酸盐、己二酸盐、藻酸盐、柠檬酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、二葡糖酸盐、环戊烷丙酸盐、十二烷基硫酸盐、乙磺酸盐、葡萄糖庚酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、富马酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙磺酸盐、乳酸盐、马来酸盐、甲磺酸盐、烟酸盐、2-萘基磺酸盐、草酸盐、双羟萘酸盐、果胶酸盐、硫氰酸盐、3-苯基丙酸盐、苦味酸盐、新戊酸盐、丙酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐和十一烷酸盐。此外，含氮的碱性基团可被如下试剂季铵盐化：烷基卤化物，如甲基、乙基、丙基、丁基的氯化物、溴化物和碘化物；二烷基硫酸盐，如二甲基、二乙基、二丁基和二戊基硫酸酯；长链卤化物如癸基、月桂基、肉豆蔻基和硬脂基的氯化物、溴化物和碘化物；芳烷基卤化物如苄基和苯乙基溴化物等。由此得到水溶性或油溶性或可分散产品。可被用于形成药学上可接受的酸加成盐的酸的例子包括如盐酸、硫酸、磷酸的无机酸，和如草酸、马来酸、甲磺酸、琥珀酸、柠檬酸的有机酸。碱加成盐可在最终分离和纯化通式I的化合物时原位制得、或使羧酸部分分别与合适的碱(如药学上可接受的金属阳离子的氢氧化物，碳酸盐或碳酸氢盐)或氨、或有机伯、仲或叔胺反应制得。药学上可接受的盐包括，但不限于，基于碱金属和碱土金属的阳离子，如钠、锂、钾、钙、镁、铝的盐等，以及无毒的铵、季铵和胺阳离子，包括，但不限于：铵、四甲基铵、四乙基铵、甲胺、二甲胺、三甲胺、三乙胺、乙胺等。其它代表性的用于形成碱加成盐的有机胺包括二乙胺、乙二胺、乙醇胺、二乙醇胺、哌嗪等。
在本发明中，术语“药学上可接受的前药”是指那些优选实施例的化合物的前药，在体内迅速转化为上述通式所示的母体化合物的化合物，例如在血液中水解。在“T.Higuchi和V.Stella，作为新型运送系统的前药(Pro-drugs as Novel DeliverySystems)，A.C.S.15Symposium Series的14卷”和“Edward B.Roche编，药物设计中的生物可逆载体(Bioreversible Carriers in Drug Design)，美国药学协会和Pergamon出版社，1987年”中提供了完整的讨论，这两者都引入本文作为参考。
本发明提供了通式(I)化合物的制备方法。两种不同的异构体可分别根据方案一和方案二中描述的制备方法获得。
其中，方案一为：
方案二为：
各式中，R1、R2、Y、n的定义如上所示。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。
下面的缩写具有如下所示的意义：
DBU是指1,8-二氮杂双环[5.4.0]十一碳-7-烯；DIBAL表示二异丁基氢化铝；DIAD指偶氮二甲酸二异丙脂；DIEA指二异丙基乙胺；DMAP是指N,N-二甲基氨基吡啶；DME指1,2-二甲氧基乙烷；DMF指N，N-二甲基甲酰胺；DMPE是指1,2-双(二甲基膦基)乙烷；DMSO表示二甲亚砜；DPPB指1,4-双(二苯基膦基)丁烷；DPPE指1,2-双(二苯基膦基)乙烷；DPPF指1,1'-双(二苯基膦基)二茂铁；DPPM指1,1'-双(二苯基膦基)甲烷EDC表示1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐；HATU表示2-(7-氮杂-1H-苯并三唑-1-基)-1,1,3,3-四甲基脲六氟磷酸盐；HMPA表示六甲基磷酰胺；IPA是指异丙醇；LDA是指二异丙基氨基锂；LHMDS是指二(三甲基硅基)氨基锂；LAH表示氢化铝锂；NCS指N-氯琥珀酰亚胺；PyBOP是指苯并三唑-1-基-氧基三吡咯烷基磷苯并三唑六氟磷酸盐；TDA-I是指三(2-(2-甲氧基乙氧基)乙基)胺；DCM指二氯甲烷；TEA是指三乙胺，TFA是指三氟乙酸；THF是指四氢呋喃；NCS指N-氯琥珀酰亚胺；NMM是指N-甲基吗啉；NMP是指N-甲基吡咯烷酮；PPh3指三苯基膦，RBF是指圆底烧瓶；r.t是指室温。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
实施例1(QBHN0174)
QBHN0174的制备过程具体如下：
第一步：中间体1
在500mL圆底烧瓶中加入5克原料A，用100mL丙酮溶解，0℃下滴加5mL JonesReagent至溶液不再由紫红色变为绿色为止，15min后升至r.t.搅拌反应1h，TLC跟踪反应结束(PMA显色)。反应毕，抽滤除去滤渣，滤液旋干后用DCM复溶，水洗2次，干燥，硅胶柱层析得5g白色固体产品(中间体1)。
第二步：中间体2
在100mL圆底烧瓶中加入5克中间体1和1.7克NH3OH·HCl，用干燥的50mLPyridine溶解，70℃下搅拌反应1～2h，TLC跟踪反应结束(PMA显色)。反应毕，旋去溶剂，DCM复溶，1N HCl水溶液洗涤2次，干燥，硅胶柱层析得5.2g淡黄色固体粗产品。
第三步：中间体3
在500mL圆底烧瓶中加入5克中间体2，用干燥的100mL MeOH溶解，0℃下加入4.2克NiCl2·6H2O，15min后分批加入2.7克NaBH4，30min后升至r.t.搅拌反应4h，TLC跟踪反应结束(PMA显色)。反应毕，抽滤除去滤渣，滤液旋干后得5g白色固体产品。
第四步：QBHN0174
在圆底烧瓶中，将0.055克中间体3、0.041克3-(4-甲基哌嗪-1-基)-丙酸、0.046克EDC、0.084mL三乙胺和0.003克DMAP溶于2mL二氯甲烷，常温反应2h，检测反应。反应毕，饱和NH4Cl水溶液洗涤2次，干燥，硅胶柱层析得25mg产品。
核磁数据为：1HNMR(400MHz,CDCl3)δ0.76(s,3H),0.80-2.30(m,36H),2.25-2.80(m,11H),3.25-4.10(m,2H),4.150-4.55(m,2H),8.60-8.70(m,5H)；质谱：[M+1]570.5
实施例1A(QBHN0174A)
QBHN0174A的制备过程具体如下：
第一步：中间体4
在氩气保护下，将0.5克知母皂苷元原料A、0.4克对硝基苯甲酸、0.63克PPh3溶于干燥的5mL THF，冰水浴中搅拌5min，再缓慢滴加DIAD，搅拌10min，撤掉冰浴，常温反应3h，检测反应。旋干溶剂，用碳酸氢钠溶液/二氯甲烷萃取，过硅胶柱纯化PE:EA＝45:1，爬板PE:EA＝15:1，香草醛显色。产率55％。
第二步：中间体5
在0.36克中间体4和0.35克K2CO3中加入15mL MeOH，温度55℃，搅拌过夜。旋干溶剂，用水/二氯甲烷萃取，将有机层旋干得产物，直接投下一步反应，香草醛显色。产率80％。
第三步：中间体6
在氩气保护下，将0.2克中间体5、0.14克邻苯二甲酰亚胺、0.25克PPh3溶于干燥的4mL THF，冰水浴中搅拌5min，再缓慢滴加0.19克DIAD，搅拌10min，撤掉冰浴，常温反应3h，检测反应。旋干溶剂，用水/二氯甲烷萃取，过硅胶柱纯化PE:EA＝45:1，爬板PE:EA＝15:1，香草醛显色，产率50％。
第四步：中间体7
在0.13克中间体6和0.072克N2H4·H2O中加入10mL MeOH，温度55℃，搅拌过夜。旋干溶剂，用水/二氯甲烷萃取，将有机层旋干得产物，直接投下一步应，香草醛显色。产率90％。
第五步：实施例1A(QBHN0174A)
在氩气保护下，将0.07克中间体、0.058克3-(4-甲基哌嗪-1-基)-丙酸、0.065克EDC和0.01克DMAP溶于4mL二氯甲烷，常温反应4h，检测反应。用碳酸氢钠溶液/二氯甲烷萃取，过碱性氧化铝柱PE:EA＝1:1。香草醛显色，产率65％。
核磁数据为：1H NMR(400MHz,CDCl3)δ8.85(d,J＝6.9Hz,1H),4.41(dd,J＝13.0,6.6Hz,1H),4.18(s,1H),3.95(d,J＝10.6Hz,1H),3.30(d,J＝11.6Hz,1H),3.01-2.20(brs,8H),2.62(d,J＝3.0Hz,2H),2.39(s,2H),2.30(s,3H),1.23-2.07(m,27H),1.08(d,J＝6.7Hz,3H),1.05–0.93(m,6H),0.76(s,3H)。
实施例1B(QBHN0174B)
QBHN0174B的制备过程具体如下：
第一步：中间体8
以原料A为起始原料，通过与实施例1A中第三步同样的条件下，获得中间体8，产率50％。
第二步：中间体9
在该步骤中，以中间体8为原料，通过与实施例1A中第四步同样的条件，获得中间体9，产率90％。
第三步：实施例1B(QBHN0174B)
在该步骤中，以中间体9和3-(4-甲基哌嗪-1-基)-丙酸为原料，通过与实施例1A中第五步同样的条件，获得实施例1B(QBHN0174B)，产率65％。
核磁数据为：1H NMR(400MHz,CDCl3)δ8.15(d,J＝7.6Hz,1H),4.33(dd,J＝14.8,7.5Hz,1H),3.88(dd,J＝10.9,2.4Hz,1H),3.65(m,1H),3.23(d,J＝10.9Hz,1H),2.90-2.10(brs,8H),2.56(t,J＝6.2Hz,2H),2.26(m,2H),2.24(s,3H),1.23-2.07(m,27H),1.01(d,J＝7.1Hz,3H),0.95–0.83(m,6H),0.69(s,3H)。
实施例2(QBHN0173)
以中间体3和1-甲基哌啶-4-甲酸为原料，通过与实施例1中第四步描述的实验步骤相同的条件，获得实施例2(QBHN0173)。
核磁数据为：1HNMR(CDCl3,400MHz):δ0.75(s,3H),0.80-2.70(m,43H),2.95-4.00(m,7H),4.40-4.55(m,1H),6.05(s,1H)；质谱：[M+1]541.5
实施例3(QBHN0177)
以中间体3和N,N-二甲基甘氨酸为原料，通过与实施例1中第四步描述的实验步骤相同的条件，获得实施例3(QBHN0177)。
核磁数据为：1HNMR(CDCl3,400MHz):δ0.76(s,3H),0.80-2.20(m,36H),2.29(s,3H),2.31(s,3H),2.80-3.00(m,2H),3.20-3.35(s,1H),3.85-4.40(m,3H),7.10-7.40(m,1H)；质谱：[M+1]501.3
实施例4(QBHN0178)
以中间体3和N,N-二甲基-Β-丙氨酸为原料，通过与实施例1中第四步描述的实验步骤相同的条件，获得实施例4(QBHN0178)。
核磁数据为：1HNMR(CDCl3,400MHz):δ0.76(s,3H),0.80-2.20(m,36H),2.32(s,3H),2.36(s,3H),2.45-2.70(m,4H),3.25-3.40(m,1H)，3.80-4.45(m,3H),8.90-9.10(m,1H)；质谱：[M+1]515.3
实施例4A(QBHN0178A)
以中间体7和N,N-二甲基-Β-丙氨酸为原料，通过与实施例1A中第五步描述的实验步骤相同的条件，获得实施例4A(QBHN0178A)。
1H NMR(400MHz,CDCl3)δ9.20(d,J＝7.8Hz,1H),4.41(dd,J＝14.1,7.6Hz,1H),4.19(d,J＝7.2Hz,1H),3.95(dd,J＝11.0,2.5Hz,1H),3.30(d,J＝10.9Hz,1H),2.59–2.50(m,2H),2.38–2.33(m,2H),2.30(s,6H),1.23-2.07(m,27H),1.08(d,J＝7.1Hz,3H),1.02–0.92(m,6H),0.76(s,3H).
实施例4B(QBHN0178B)
以中间体9和N,N-二甲基-Β-丙氨酸为原料，通过与实施例1A中第五步描述的实验步骤相同的条件，获得实施例4B(QBHN0178B)。
1H NMR(400MHz,CDCl3)δ7.77(d,J＝7.2Hz,1H),4.41(dd,J＝14.1,7.5Hz,1H),3.95(dd,J＝10.9,2.3Hz,1H),3.78–3.65(m,1H),3.30(d,J＝11.0Hz,1H),2.53(t,J＝6.2Hz,2H),2.32(t,J＝6.2Hz,2H),2.27(s,6H),1.23-2.07(m,27H),1.08(d,J＝7.1Hz,3H),1.02–0.93(m,6H),0.76(s,3H).
实施例5(QBHN0180)
以中间体3和3-oxo-3-(4-甲基哌嗪-1-基)丙酸为原料，通过与实施例1中第四步描述的实验步骤相同的条件，获得实施例5(QBHN0180)。
核磁数据为：1HNMR(CDCl3,400MHz):δ0.76(s,3H),0.80-2.20(m,36H),2.40(s,3H)，2.55-2.70(m,4H),3.25-4.20(m,9H),4.45-4.55(m,1H)；质谱：[M+1]584.3
实施例6(QBHN0185)
以中间体3和3-oxo-3-(1-甲基哌嗪-4-氨基)丙酸为原料，通过与实施例1中第四步描述的实验步骤相同的条件，获得实施例6(QBHN0185)。
核磁数据为：1HNMR(CDCl3,400MHz):δ0.76(s,3H),0.80-2.20(m,40H),2.75-3.70(m,12H),3.25-3.70(m,2H),3.84-4.40(m,3H),7.60-7.80(m,5H)；质谱：[M+1]598.3
实施例7(QBHN0186)
以中间体3和3-oxo-3-(1-甲基哌啶-4-甲基氨基)丙酸为原料，通过与实施例1中第四步描述的实验步骤相同的条件，获得实施例7(QBHN0186)。
核磁数据为：1HNMR(CDCl3,400MHz):δ0.76(s,3H),0.80-2.30(m,41H),2.75-3.00(m,4H),3.25-3.70(m,11H),3.84-4.40(m,2H),7.60-7.70(m,1H)；质谱：[M+1]612.3
实施例8(QBHN0187)
以中间体3和3-oxo-3-(3-吗啉丙基)氨基丙酸为原料，通过与实施例1中第四步描述的实验步骤相同的条件，获得实施例8(QBHN0187)。
核磁数据为：1HNMR(CDCl3,400MHz):δ0.75(s,3H),0.80-2.30(m,38H),2.45-2.60(m,4H),3.25-4.00(m,13H),4.10-4.55(m,2H),7.60-7.80(m,1H)；质谱：[M+1]628.3
实施例9(QBHN0190)
以中间体3和3-oxo-3-(1,4-双哌啶-1-)丙酸为原料，通过与实施例1第四步中描述的实验步骤相同的条件，获得实施例9(QBHN0190)。
核磁数据为：1HNMR(CDCl3,400MHz,ppm):δ0.76(s,3H),0.80-2.30(m,46H),2.55-3.60(m,10H),3.75-4.55(m,5H),7.20-7.40(m,1H)；质谱：[M+1]652.3
实施例10(QBHN0191)
以中间体3和3-oxo-3-(哌嗪-1-)丙酸为原料，通过与实施例1中第四步描述的实验步骤相同的条件，获得实施例10(QBHN0191)。
核磁数据为：1HNMR(CDCl3,400MHz):δ0.77(s,3H),0.80-2.20(m,36H),2.85-4.00(m,13H),4.40-4.55(m,1H),7.40-7.40(m,1H)；质谱：[M+1]570.3
实施例11(QBHN0192)
以中间体3和3-(六氢吡咯并[3,4-c]吡咯-2(1H)-基)-3-氧代丙酸(英文名称：3-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-oxopropanoic acid)为原料，通过与实施例1中第四步描述的实验步骤相同的条件，获得实施例11(QBHN0192)。
核磁数据为:1HNMR(CDCl3,400MHz):δ0.76(s,3H),0.80-2.20(m,38H),2.95-4.00(m,13H),4.40-4.55(m,1H),7.20-7.50(m,2H)；质谱：[M+1]596.4
实施例12(QBHN0199)
以中间体3和3-氧-3-(4-(2-(吡喏烷-1-基)乙基)哌嗪-1-基)丙酸(英文名称：3-oxo-3-(4-(2-(pyrrolidin-1-yl)ethyl)piperazin-1-yl)propanoic acid)为原料，通过与实施例1中第四步描述的实验步骤相同的条件，获得实施例12(QBHN0199)。
核磁数据为:1HNMR(CDCl3,400MHz):δ0.74(s,3H),0.80-2.30(m,36H),2.45-2.80(m,8H),3.25-4.00(m,11H),4.10-4.45(m,2H)；质谱：[M+1]667.5
实施例13化合物活性测试
CTG细胞增殖实验-知母皂苷衍生物抑制多种肿瘤细胞体外生长
肿瘤细胞包括：人A549细胞(肺癌细胞)(ATCC，产品目录号CCL-185)、HeLa细胞(宫颈癌细胞)(ATCC，产品目录号CCL-2)、HepG2细胞(肝癌细胞)(ATCC，产品目录号HB-8065)、A375细胞(黑色素瘤细胞)(ATCC，产品目录号CRL-1619)、MCF-7(乳腺癌细胞)(ATCC，产品目录号HTB-22)和U87MG(脑胶质瘤细胞)(ATCC，产品目录号HTB-14)、LN229(ATCC，产品目录号CRL-2611)、A172(ATCC，产品目录号CRL-1620)、KNS-42(JCRB，产品目录号IFO50356)，BE(2)-C(ATCC，产品目录号CRL-2268)、U118MG(ATCC，产品目录号HTB-15)、SW-1088(ATCC，产品目录号HTB-12)、SH-SY5Y(CLS，产品目录号300154)。
具体过程为：
将上述肿瘤细胞按每孔(1.8～15)×103个接种至含有特定培养基的底透壁白的96-孔培养板(Corning，产品目录号CLS3903)中，置于37℃、5％CO2培养箱内培养24小时。
各个化合物用DMSO(Sigma，产品目录号D2650)配成10mM的储备液，用培养基稀释至所需浓度(DMSO终浓度为0.2％)后加入各孔，2孔/浓度，在37℃、5％CO2培养箱内孵育72小时。之后，每孔加入100μl
细胞活性检测试剂(Promega，产品目录号G7573)，在振板机上混匀10分钟，诱导细胞溶解。将96孔板在室温中放置10分钟，使其发光信号稳定。粘贴白色的底膜于培养板底部，使用EnSpire测板。通过XLfit软件进行数据处理，获得IC50值。
上述知母皂苷衍生物显著抑制多种肿瘤细胞体外生长的实验结果见表1～2。
表1.实施例对A549肺癌细胞体外生长的抑制
表2.实施例对脑瘤细胞体外生长的抑制(IC50，μM)
| 实施例 | U87MG | LN229 | A172 | KNS-42 | BE(2)-C | U118MG | SW-1088 | SH-SY5Y |
| 2 | 1.57 | 1.58 | 2.76 | 1.59 | 3.19 | 1.87 | 0.49 | 1.56 |
| 2A | 1.56 | 1.62 | 1.66 | 1.77 | 2.85 | 1.07 | 0.66 | 2.78 |
| 2B | 4.66 | 5.52 | 3.84 | 4.78 | 7.9 | 5.17 | 2.75 | >10 |
| 4 | 2.36 | 2.29 | 3.04 | 1.92 | 3.31 | 1.93 | 2.72 | 2.8 |
| QBHN0221 | 2.7 | 2.6 | 3.38 | 5.16 | 4.18 | 2.28 | 3.88 | 3.22 |
表一和表二显示本发明的化合物对多种肿瘤细胞的生长有着高抑制活性，特别是对各种脑瘤细胞(表二)具有广泛的抑制活性，一些化合物的活性优于对照化合物QBHN0221(表二)。
在此说明书中，本发明已参照其特定的实施例作了描述。但是，很显然仍可以做出各种修改和变换而不背离本发明的精神和范围。因此，说明书应被认为是说明性的而非限制性的。
Claims (10)
1.一种基于知母菝契皂苷元结构的衍生物，其特征在于，所述的衍生物的结构式如通式I所示，
其中，Z为NR1R2；R1和R2各自独立地为氢、取代或未取代的C1-C10烷基，C1-C10烷基的取代基选自卤素、羟基、-NH2、硝基、-CN、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基、C3-C6环烷基、C2-C4链烯基、C2-C4炔基、苯基、苄基；或者R1和R2一起形成三至八元环，所述的三至八元环具有一个或多个选自C1-C10烷基、C3-C10环烷基、C6-C20芳基、或C3-C14杂芳基、卤素、羟基、氨基、烷氧基、-CF3、-SF5或杂原子为硫、氧、NH或NRa的三至八元杂环的取代基；
X为C(O)或S(O)2；
Y为C(Rd)(Re)、C(O)或S(O)2，Rd、Re独立地为无取代基或具有至少一个取代基的C1-C10烷基、C3-C10环烷基、C6-C20芳基、或C3-C14杂芳基，其中的取代基选自卤素、羟基、氨基、硝基、氰基、醛基、羧基、烷氧基、-CF3或-SF5，或者，Rd和Re一起形成三至八元环；
Ra独立地为无取代基或具有至少一个取代基的C1-C10烷基、C3-C10环烷基、C6-C20芳基、或C3-C14杂芳基，其中的取代基选自卤素、羟基、氨基、硝基、氰基、烷氧基、-CF3或-SF5；
n为0至10的整数且n不为0，m为1，或者，n为0，m为1，或者，n为0至10的整数且n不为0，m为0；
所述的衍生物中的一个或多个氢原子可选氘原子取代。
2.一种基于知母菝契皂苷元结构的衍生物，其特征在于，所述的衍生物的结构式如通式II所示，
R1和R2各自独立地为氢、取代或未取代的C1-C10烷基，C1-C10烷基的取代基选自卤素、羟基、-NH2、硝基、-CN、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基、C3-C6环烷基、C2-C4链烯基、C2-C4炔基、苯基、苄基；或者R1和R2一起形成三至八元环，所述的三至八元环具有一个或多个选自C1-C10烷基、C3-C10环烷基、C6-C20芳基、或C3-C14杂芳基、卤素、羟基、氨基、硝基、氰基、烷氧基、-CF3、-SF5或杂原子为硫、氧、NH或NRa的三至八元杂环的取代基；
Y为C(Rd)(Re)或C(O)，Rd、Re独立地为无取代基或包括至少一个取代基的C1-C10烷基、C3-C10环烷基、C6-C20芳基、或C3-C14杂芳基，其中的取代基选自卤素、羟基、氨基、硝基、氰基、烷氧基、-CF3或-SF5，或者，Rd和Re一起形成三至八元环；
n为0至10的整数。
3.一种基于知母菝契皂苷元结构的衍生物，其特征在于，所述的衍生物的结构式如通式III所示，
R1和R2各自独立地为氢、取代或未取代的C1-C10烷基，C1-C10烷基的取代基选自卤素、羟基、-NH2、硝基、-CN、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基、C3-C6环烷基、C2-C4链烯基、C2-C4炔基、苯基、苄基；或者R1和R2一起形成三至八元环，所述的三至八元环具有一个或多个选自C1-C10烷基、C3-C10环烷基、C6-C20芳基、或C3-C14杂芳基、卤素、羟基、氨基、烷氧基、-CF3、-SF5或杂原子为硫、氧、NH或NRa的三至八元杂环的取代基；
n为0至10的整数。
4.一种基于知母菝契皂苷元结构的衍生物，其特征在于，所述的衍生物的结构式如通式IV所示，
R1和R2各自独立地为氢、取代或未取代的C1-C10烷基，C1-C10烷基的取代基选自卤素、羟基、-NH2、硝基、-CN、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基、C3-C6环烷基、C2-C4链烯基、C2-C4炔基、苯基、苄基；或者R1和R2一起形成三至八元环，所述的三至八元环具有一个或多个选自C1-C10烷基、C3-C10环烷基、C6-C20芳基、或C3-C14杂芳基、卤素、羟基、氨基、烷氧基、-CF3、-SF5或杂原子为硫、氧、NH或NRa的三至八元杂环的取代基；
n为0至10的整数。
5.一种基于知母菝契皂苷元结构的衍生物，其特征在于，所述的衍生物为以下化合物、以下化合物的非对映异构体混合物或以下化合物的对映异构体中的一种，
6.一种药物组合物，其特征在于，所述的药物组合物包括第一成分或第一成分与第二成分的组合，
所述的第一成分为根据权利要求1至5任一项所述的基于知母菝契皂苷元结构的衍生物、其药学上可接受的盐、立体异构体、互变异构体和其药学上可接受的载体；
所述的第二成分为抗肿瘤药物，所述的抗肿瘤药物包括化疗药物、靶向肿瘤治疗药物或肿瘤治疗抗体药物中的一种或多种。
7.根据权利要求6所述的药物组合物，其特征在于，所述的药学上可接受的盐选自盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、1-萘磺酸盐、2-萘磺酸盐、乙酸盐、三氟乙酸盐、苹果酸盐、酒石酸盐、柠檬酸盐、乳酸盐、草酸盐、琥珀酸盐、富马酸盐、马来酸盐、苯甲酸盐、水杨酸盐、苯乙酸盐或扁桃酸盐的一种或多种；
所述的抗肿瘤药物为PD-1抗体、CTLA-4抗体、PD-L1抗体或PD-L2抗体的一种或多种。
8.一种根据权利要求6或7中所述的药物组合物在制备治疗癌症的药物中的应用。
9.根据权利要求8所述的应用，其特征在于，所述的癌症包括：结肠癌、乳腺癌、胃癌、肺癌、大肠癌、胰腺癌、卵巢癌、前列腺癌、肾癌、肝癌、脑癌、黑色素瘤、慢性粒细胞性白血病、血液肿瘤或其他远离肿瘤原发部位的组织或器官的转移病变。
10.根据权利要求9所述的应用，其特征在于，所述的血液肿瘤为淋巴肿瘤或多发性骨髓瘤。
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